BMC Pharmacology and Toxicology volume 13, Article number: A44 (2012)
Recent evidence suggests that high-frequency deep brain stimulation of the nucleus accumbens (NAcb-DBS) may represent a novel therapeutic strategy for individuals suffering from treatment-resistant depression although the underlying mechanism of action remains largely unknown. Using a unique psychopathological mouse model of enhanced depression- and anxiety-like behavior (HAB) we investigated behavioral and neurobiological effects of NAcb-DBS.
HAB mice underwent either chronic treatment with different selective serotonin reuptake inhibitors (SSRIs) or stereotactic surgery to implant DBS electrodes into the NAcb. NAcb-DBS was applied for 1 h daily for seven consecutive days (130 Hz, 100 µA, 60 µs pulse width) and sham-stimulated animals were used as controls. Anxiety- and depression-related behaviors were assessed using established tests with predictive anxiolytic or antidepressant validity. Furthermore, the effects of NAcb-DBS on challenge-induced immediate early gene expression and hippocampal neurogenesis were investigated.
Chronic SSRI treatment did not alter the enhanced depression-like behavior of HAB mice, while repeated, but not single, NAcb-DBS induced robust antidepressant and anxiolytic responses. Interestingly, NAcb-DBS did not affect behavior in normal depression/anxiety animals (NAB), suggesting a preferential effect of NAcb-DBS on pathophysiologically deranged systems. Antidepressant-like effects of NAcb-DBS were associated with normalization of challenge-induced dentate gyrus hypoactivity and modulation of neuronal activity in various brain regions implicated in stress and depression. Furthermore, NAcb-DBS enhanced the blunted hippocampal neurogenesis in HABs.
Taken together we show that the normalization of pathophysiologically enhanced depression-like behavior by repeated NAcb-DBS was associated with normalization of aberrant brain activity and rescue of impaired adult neurogenesis, indicating that DBS affects gene expression as well as neuronal plasticity in a defined, mood-associated network. Finally, it is suggested that SSRI-insensitive HAB mice represent a clinically relevant model for elucidating the neurobiological correlates underlying the observed behavioral effects of NAcb-DBS.
Supported by the Hope for Depression Research Foundation (HDRF/ISAN) and the Austrian Science Fund FWF DK SPIN (W1206).
Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Schmuckermair, C., Gaburro, S., Sah, A. et al. Neurobiological correlates of successful deep brain stimulation in a mouse model of high trait affect. BMC Pharmacol Toxicol 13 (Suppl 1), A44 (2012). https://doi.org/10.1186/2050-6511-13-S1-A44
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DOI: https://doi.org/10.1186/2050-6511-13-S1-A44